US20230118503A1 - NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES - Google Patents

NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES Download PDF

Info

Publication number
US20230118503A1
US20230118503A1 US17/978,442 US202217978442A US2023118503A1 US 20230118503 A1 US20230118503 A1 US 20230118503A1 US 202217978442 A US202217978442 A US 202217978442A US 2023118503 A1 US2023118503 A1 US 2023118503A1
Authority
US
United States
Prior art keywords
glaucoma
prophylaxis
treatment
macular
dystrophy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US17/978,442
Inventor
Christopher Turski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US17/978,442 priority Critical patent/US20230118503A1/en
Publication of US20230118503A1 publication Critical patent/US20230118503A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • COE-1 endothelin converting enzyme-1
  • NEP neutral endopeptidase
  • hSEP human soluble endopeptidase
  • netarsudil netarsudil, adenosine A 1 receptor agonists such as e.g. trabodenoson, ET A endothelin receptor antagonists such as e.g. sitaxentan, dual endothelin receptor antagonists such as e.g. bosentan, nitric oxide donors such as e.g. butanediol, parasympathomimetics such as e.g. pilocarpine, acetylcholine, catecholamines such as e.g. adrenaline, muscarinic receptor antagonists such as e.g. atropine, vascular endothelial growth factor inhibitors such as e.g. ranibizumab, corticosteroids such as e.g.
  • dexamethasone antibiotics such as e.g. vancomycin, tissue regenerating agents such as e.g. poly-carboxymethylglucose, vitamins and provitamins such as e.g. panthenol and retinyl palmitate, chemotherapeutic agents such as e.g. mitomycin, nonsteroidal anti-inflammatory drugs such as e.g. ketorolac, H 1 receptor antagonists such as e.g. cetirizine, monoclonal antibodies such as e.g. adalimumab, proteases such as e.g. ocriplasmin, immunosuppressive agents such as e.g. cyclosporine, or none, for prophylaxis and/or treatment of eye diseases.
  • antibiotics such as e.g. vancomycin
  • tissue regenerating agents such as e.g. poly-carboxymethylglucose
  • vitamins and provitamins such as e.g. panthenol and
  • Glaucoma is the most common optic nerve head neuropathy and is associated morphologically with loss of retinal ganglion cells and clinically with visual field deterioration. Treatment of glaucoma is based on lowering of intraocular pressure and preventing the occurrence or progression of optic neuropathy. No therapy is currently available to mitigate ocular blood flow changes during glaucoma, or to limit the death of retinal ganglion cells by means of apoptosis in the course of glaucoma (B. C. Chauhan (2008) Can. J. Ophthalmol. 43, 356-360).
  • Endothelin is the human body's most potent vasoactive peptide known to date. As connoted by the term vasoactive peptide, this peptide participates in the regulation of intraocular blood pressure by means of vasoconstrictor activity. Upon release it causes a decrease in ocular blood flow followed by pathology in the retina and the optic nerve head.
  • Endothelin apart from its vasoconstrictor activity, participates in the regulation of intraocular pressure by means of affecting trabecular outflow, which is the main route for fluid outflow from the eye. Endothelin increases contractility of the trabecular meshwork and therefore decreases fluid outflow from the eye elevating intraocular pressure followed by pathology in the retina and the optic nerve head.
  • Endothelin apart from affecting intraocular blood pressure and regulating intraocular fluid pressure, influences apoptosis of retinal ganglion cells acting via ET B receptors and induces proliferation of human optic nerve head astrocytes acting via both ET A and ET B receptors (G. Prasanna, R. Krishnamoorthy, A. F. Clark, R. J. Wordinger & T. Yorio (2002) Invest. Ophthalmol. Vis. Sci. 43, 2704-2713).
  • Endothelin is a peptide composed of 21 amino acids that is synthesized and released by the endothelium. Endothelin is produced by cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET-1). Endothelin converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, catalyses proteolytic activation of Big endothelin-1 to ET-1 and constitutes a regulatory site controlling production of the active peptide.
  • ECE-1 Endothelin converting enzyme-1
  • Neutral endopeptidase a zink metallopeptidase, degrades atrial natriuretic peptide (ANP) and constitutes a regulatory site controlling concentration of the active peptide.
  • ANP inhibits apoptosis by causing cGMP elevation.
  • Spreading depression in the cortex is followed by long lasting elevation of the ANP expression and intracellular cGMP concentration.
  • Natriuretic peptide receptor NPrA regulates intracellular cGMP concentration by stimulating particulate guanylyl cyclase (pGC), which activates cGMP-dependent protein kinase G pathway.
  • the invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity.
  • NEP neutral endopeptidase
  • hSEP human soluble endopeptidase
  • the invention relates to the use of compounds disclosed in the patent EP1706121 B1 for the manufacture of medicaments giving a beneficial effect.
  • a beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the invention also relates to the use of compounds of the invention for the manufacture of medicaments for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • specific compounds disclosed herein are used for the manufacture of a medication.
  • EP1706121 B1 refers to the use of certain compounds with a combined inhibitory activity on both neutral endopeptidase, and/or human soluble endopeptidase (hSEP), and endothelin converting enzyme (ECE) for the treatment and/or prophylaxis of neurodegenerative diseases such as traumatic brain injury, acute disseminated encephalomyelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage, and for prophylaxis of ischemic stroke, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.
  • neurodegenerative diseases such as traumatic brain injury, acute disseminated encephalomyelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage,
  • WO 2004/082637 filed on Mar. 18, 2004, and published on Sep. 30, 2004, discloses a method for the prophylaxis or treatment of a very large number of pathological conditions, comprising administering an aldosterone receptor antagonist and an ECE inhibitor.
  • pathological conditions listed are glaucoma, hypertensive or diabetic retinopathy, and elevated intraocular pressure.
  • no disclosure regarding the benefit of preferred compounds in these indications was made.
  • the goal of the present invention was to identify specific metalloprotease inhibitors which are of therapeutic value when administered in a pharmaceutical composition not containing aldosterone receptor antagonist.
  • benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity prevent apoptosis in rodent models similar to that observed in the course of eye diseases in humans.
  • NEP neutral endopeptidase
  • hSEP human soluble endopeptidase
  • primary and secondary glaucoma preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma; (ii) aquired macular disorders, preferably such as e.g.
  • optic neuropathy preferably such as e.g. anterior or posterior ischemic optic neuropathy
  • optic neuritis preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis
  • hereditary fundus dystrophies preferably such as e.g.
  • retinal vascular diseases preferably such as e.g.
  • diabetic retinopathy non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischaemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy; (viii) scleritis and episcleritis; (ix) retinal detachments; (x) trauma to the eye globe; (xi) vitreous opacities, preferably such as e.g.
  • vitreous hemorrhage, and asteroid hyalosis preferably myopia and degenerative myopia;
  • postsurgical trauma preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery;
  • xiv dry eye disease;
  • corneal disorders preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation; and corneal ectasias, preferably such as keratoconus.
  • A represents CH2, O or S,
  • compositions of the present invention may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable metal cation or an organic base, for instance an amine.
  • Preferred bivalent metal salts are calcium, magnesium and zinc salts. Most preferred is the calcium salt.
  • the invention relates to the use of a compound of general formula (1), as defined above, for treatment and/or prophylaxis and/or preparation of pharmaceutical compositions for treatment and/or prophylaxis of optic and/or eye diseases selected from the group consisting of such diseases as e.g. (i) all forms of primary and secondary glaucoma, preferably such as e.g.
  • aquired macular disorders preferably such as e.g.
  • optic neuropathy preferably such as e.g. anterior or posterior ischemic optic neuropathy
  • optic neuritis preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis
  • hereditary fundus dystrophies preferably such as e.g.
  • retinal vascular diseases preferably such as e.g.
  • diabetic retinopathy non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischaemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy; (viii) scleritis and episcleritis; (ix) retinal detachments; (x) trauma to the eye globe; (xi) vitreous opacities, preferably such as e.g.
  • vitreous hemorrhage, and asteroid hyalosis preferably myopia and degenerative myopia;
  • postsurgical trauma preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery;
  • xiv dry eye disease;
  • corneal disorders preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation; and corneal ectasias, preferably such as keratoconus, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.
  • the invention particularly relates to the use of compounds having general formula (4):
  • the most preferred active substances used according to the present invention are:
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquids or carrier materials.
  • the pharmaceutical compositions of the invention may be administered either topically and/or systemically and in particular e.g. topically to the eye, periocularly in such manner as subconjunctival, subtenon, retrobulbar or peribulbar, intraocularly into the eye, but also enterally, orally, parenterally (intramuscularly or intravenously), subcutaneously or rectally.
  • compositions can be administered in the form of solutions, suspensions, ointments (creams, gels, gel-forming solutions, sprays, ocular inserts/deposits, contact lenses), ocular implants but also tablets, capsules, softgels, powders, suppositories, nano-formulations or via iontophoresis, or by means of pharmaceutical compositions based on nanoparticle carrier systems.
  • Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
  • Compounds of the present invention are generally administered as pharmaceutical compositions.
  • Types of pharmaceutical compositions that may be used include but are not limited to solutions, suspensions, ointments (creams, gels or sprays), but also tablets, chewable tablets, capsules, softgels, parenteral solutions, suppositories, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the pharmaceutical compositions of the invention do not contain an aldosterone receptor antagonist.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention.
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • Apoptosis is a significant component of cell death in optic and/or eye diseases including (i) all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma (R. Agarwal, S. K. Gupta, P. Agarwal, R.
  • primary open-angle glaucoma preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dis
  • aquired macular disorders preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, and microcystic macular oedema (J. L. Dunaief, T. Dentchev, G.-S. Ying & A. H. Milam (2002) Arch. Ophthalmol.
  • optic neuropathy preferably such as e.g. anterior or posterior ischemic optic neuropathy (B. J. Slater, Z. Mehrabian, Y. Guo, A. Hunter & S. L. Bernstein (2008) Invest. Ophthalmol. Vis. Sci. 49, 3671-3676);
  • optic neuritis K. S. Shindler, E. Ventura, M. Dutt & A. Rostami (2008) Exp. Eye Res. 87, 208-213);
  • uveitis preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis (C.-C. Chan, D. M.
  • hereditary fundus dystrophies preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy (H. Zhang, X. Li, X. Dai, J. Han, Y.
  • retinal vascular diseases preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy (G. Donati, A.
  • vitreous opacities such as e.g. vitreous haemorrhage and asteroid hyalosis (A. Alamri, H. Alkatan & I. Aljadaan (2016) Middle East African J. Ophthalmol. 23, 271-273);
  • xii myopia and degenerative myopia (G. Z. Xu, W. W. Li & M. O. Tso (1996) Trans. Am. Ophthalmol. Soc.
  • postsurgical trauma preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery (A. Barak, T. Goldkorn & L. S. Morse (2005) Invest. Ophthalmol. Vis. Sci. 46, 2587-2591; X. Liu, S. Ling, X. Gao, C. Xu & F. Wang (2013) JAMA Ophthalmol. 131, 1070-1072; D. Reichstein (2015) Curr. Opin. Ophthalmol. 26, 157-166); (xiv) dry eye disease (S. Yeh, X.J. Song, D. Q. Li, W. Farley, M. E.
  • corneal disorders preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation, and corneal ectasias, preferably such as keratoconus (R. M. Kaldawy, J. Wagner, S. Ching & G. M. Seigel (2002) Cornea 21, 206-209; N. Szentmary, B. Szende & I. Suveges (2005) Eur. J. Ophthalmol.
  • rats are subjected to systemic administration of doxorubicin and apoptosis assessed in large organs such as the liver or heart (R. Gillet, G. Grimber, M. Bennoun, C. Caron de Fromentel, P. Briand & V. Joulin (2000) Oncogene 19, 3498-3507; L.L. Fan, G. P. Sun, W. Wei, Z. G. Wang, L. Ge, W. Z. Fu & H. Wang (2010) World J. Gastroenterol.
  • doxorubicin in the eye and apoptosis assessed in the retinal ganglion cells (I. M. Parhad, J. W. Griffin, A. W. Clark & J. F. Koves (1984) J. Neuropathol. Exp. Neurol. 43, 188-200).
  • Wistar rats, 200-250 g were anesthetized with chloral hydrate, 400 mg/kg, and osmotic minipumps, primed prior to implantation, were filled with either vehicle or example (6), representative for the compounds of the invention, in the dose of 60 mg/kg/d, and were implanted subcutaneously.
  • Rats were euthanized 5 days after the first i.p. injection of doxorubicin, or 5 days after the administration of doxorubicin into the vitreous body, and were transcardially perfused with a solution containing 4% paraformaldehyde in phosphate buffer. The livers and the eyes were subsequently removed and embedded in paraffin. To visualize apoptosis, a terminal deoxynucleotide transferase-mediated dUTP nick end-label (TUNEL) based staining was performed on 10 ⁇ m paraffin sections. The method of stereological disector (L. M. Cruz-Orive & E. R. Weibel (1990) Am. J. Physiol.
  • L148-L156 was used for quantification of apoptosis.
  • An unbiased counting frame (0.05 ⁇ 0.05 mm, disector height 0.01 mm) was used for liver and (0.10 ⁇ 0.025 mm, disector height 0.01 mm) for the retinal ganglion cell layer for the sampling.
  • the N v of TUNEL positive cells was determined with 8-10 dissectors and is expressed as number of TUNEL positive cells ⁇ 10 2 /mm 3 for liver and as number of TUNEL positive cells ⁇ 10 3 /mm 3 for retinal ganglion cells.
  • Statistical evaluation was performed by means of Student's t-test (Table 1).
  • Example (6) decreased density of apoptotic cells in the rat liver by 23.46% and in the retina by 8.21% (Table 1).
  • the apoptosis induced by doxorubicin in the liver was characterized by many morphological features similar to those of apoptosis seen in the retinal ganglion cells.

Abstract

The invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having both neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP), and endothelin convertase (ECE) inhibitory activity. The compounds of the invention are useful for the preparation of pharmaceutical compositions for prophylaxis and treatment of eye diseases.

Description

    FIELD OF THE INVENTION
  • Described are dual inhibitors of endothelin converting enzyme-1 (ECE-1), and neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) alone, and compositions thereof, with the proviso that said pharmaceutical compositions may optionally contain either one or more of carbonic anhydrase inhibitors such as e.g. brinzolamide, α2-adrenergic agonists such as e.g. brimonidine, β-blockers such as e.g. timolol, prostaglandin analogs such as e.g. bimatoprost, rho kinase inhibitors such as e.g. netarsudil, adenosine A1 receptor agonists such as e.g. trabodenoson, ETA endothelin receptor antagonists such as e.g. sitaxentan, dual endothelin receptor antagonists such as e.g. bosentan, nitric oxide donors such as e.g. butanediol, parasympathomimetics such as e.g. pilocarpine, acetylcholine, catecholamines such as e.g. adrenaline, muscarinic receptor antagonists such as e.g. atropine, vascular endothelial growth factor inhibitors such as e.g. ranibizumab, corticosteroids such as e.g. dexamethasone, antibiotics such as e.g. vancomycin, tissue regenerating agents such as e.g. poly-carboxymethylglucose, vitamins and provitamins such as e.g. panthenol and retinyl palmitate, chemotherapeutic agents such as e.g. mitomycin, nonsteroidal anti-inflammatory drugs such as e.g. ketorolac, H1 receptor antagonists such as e.g. cetirizine, monoclonal antibodies such as e.g. adalimumab, proteases such as e.g. ocriplasmin, immunosuppressive agents such as e.g. cyclosporine, or none, for prophylaxis and/or treatment of eye diseases.
    • SCIENTIFIC BACKGROUND OF THE INVENTION
  • An increased intraocular pressure and reduced ocular blood flow are the major risk factors for glaucoma in humans. Glaucoma is the most common optic nerve head neuropathy and is associated morphologically with loss of retinal ganglion cells and clinically with visual field deterioration. Treatment of glaucoma is based on lowering of intraocular pressure and preventing the occurrence or progression of optic neuropathy. No therapy is currently available to mitigate ocular blood flow changes during glaucoma, or to limit the death of retinal ganglion cells by means of apoptosis in the course of glaucoma (B. C. Chauhan (2008) Can. J. Ophthalmol. 43, 356-360).
  • Endothelin is the human body's most potent vasoactive peptide known to date. As connoted by the term vasoactive peptide, this peptide participates in the regulation of intraocular blood pressure by means of vasoconstrictor activity. Upon release it causes a decrease in ocular blood flow followed by pathology in the retina and the optic nerve head.
  • Endothelin, apart from its vasoconstrictor activity, participates in the regulation of intraocular pressure by means of affecting trabecular outflow, which is the main route for fluid outflow from the eye. Endothelin increases contractility of the trabecular meshwork and therefore decreases fluid outflow from the eye elevating intraocular pressure followed by pathology in the retina and the optic nerve head.
  • Endothelin, apart from affecting intraocular blood pressure and regulating intraocular fluid pressure, influences apoptosis of retinal ganglion cells acting via ETB receptors and induces proliferation of human optic nerve head astrocytes acting via both ETA and ETB receptors (G. Prasanna, R. Krishnamoorthy, A. F. Clark, R. J. Wordinger & T. Yorio (2002) Invest. Ophthalmol. Vis. Sci. 43, 2704-2713).
  • Endothelin is a peptide composed of 21 amino acids that is synthesized and released by the endothelium. Endothelin is produced by cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET-1). Endothelin converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, catalyses proteolytic activation of Big endothelin-1 to ET-1 and constitutes a regulatory site controlling production of the active peptide.
  • Neutral endopeptidase (NEP), a zink metallopeptidase, degrades atrial natriuretic peptide (ANP) and constitutes a regulatory site controlling concentration of the active peptide. In serum-deprived pheochromocytoma cells, ANP inhibits apoptosis by causing cGMP elevation. Spreading depression in the cortex is followed by long lasting elevation of the ANP expression and intracellular cGMP concentration. Natriuretic peptide receptor NPrA regulates intracellular cGMP concentration by stimulating particulate guanylyl cyclase (pGC), which activates cGMP-dependent protein kinase G pathway.
  • Since up-regulation of ET-1 receptors and down-regulation of ANP receptors has been reported to occur in cells subjected to metabolic or oxidative insults, it prompted us to explore the effects of dual ECE/NEP inhibition on rodent cells undergoing apoptosis similar to those reported in humans during ophthalmic diseases such as during e.g. glaucoma.
    • INDUSTRIAL BACKGROUND OF THE INVENTION
  • The invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity. The compounds of the invention are useful for the preparation of pharmaceutical compositions for prophylaxis and treatment of ophthalmic diseases.
  • The invention relates to the use of compounds disclosed in the patent EP1706121 B1 for the manufacture of medicaments giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of compounds of the invention for the manufacture of medicaments for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medication.
  • EP1706121 B1 refers to the use of certain compounds with a combined inhibitory activity on both neutral endopeptidase, and/or human soluble endopeptidase (hSEP), and endothelin converting enzyme (ECE) for the treatment and/or prophylaxis of neurodegenerative diseases such as traumatic brain injury, acute disseminated encephalomyelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage, and for prophylaxis of ischemic stroke, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.
  • WO 2004/082637, filed on Mar. 18, 2004, and published on Sep. 30, 2004, discloses a method for the prophylaxis or treatment of a very large number of pathological conditions, comprising administering an aldosterone receptor antagonist and an ECE inhibitor. Among the pathological conditions listed are glaucoma, hypertensive or diabetic retinopathy, and elevated intraocular pressure. However, no disclosure regarding the benefit of preferred compounds in these indications was made.
  • The goal of the present invention was to identify specific metalloprotease inhibitors which are of therapeutic value when administered in a pharmaceutical composition not containing aldosterone receptor antagonist.
  • Surprisingly, it now has been found that benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity prevent apoptosis in rodent models similar to that observed in the course of eye diseases in humans. This property makes them useful for treatment and/or prophylaxis and/or preparation of pharmaceutical compositions for treatment and/or prophylaxis of optic and/or eye diseases selected from the group consisting of such diseases as e.g. (i) all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma; (ii) aquired macular disorders, preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, and microcystic macular oedema; (iii) optic neuropathy, preferably such as e.g. anterior or posterior ischemic optic neuropathy; (iv) optic neuritis; (v) uveitis, preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis; (vi) hereditary fundus dystrophies, preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy; (vii) retinal vascular diseases, preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischaemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy; (viii) scleritis and episcleritis; (ix) retinal detachments; (x) trauma to the eye globe; (xi) vitreous opacities, preferably such as e.g. vitreous hemorrhage, and asteroid hyalosis; (xii) myopia and degenerative myopia; (xiii) postsurgical trauma, preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery; (xiv) dry eye disease; (xv) corneal disorders, preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation; and corneal ectasias, preferably such as keratoconus.
  • The compounds of the invention are known from the European patents EP 0 733 642, EP 0 916 679 and EP 1 468 010, containing detailed syntheses, and can be described by the general formula (1):
  • Figure US20230118503A1-20230420-C00001
  • wherein:
    • R1 stands for a group with formula (2) or (3):
  • Figure US20230118503A1-20230420-C00002
  • A represents CH2, O or S,
    • R2 and R3 independently represent hydrogen or halogen,
    • R4 and R6 independently represent hydrogen or a biolabile carboxylic ester forming group;
    • R5 is selected from the group consisting of (C1-C6)-alkoxy-(C1-C6)-alkyl which may be substituted by a (C1-C6)-alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy or halogen, and naphtyl-(C1-C6)-alkyl,
    • R7 and R8 independently represent hydrogen or a group forming a biolabile phosphonic acid ester.
  • To the invention belong all compounds having formula (1), racemates, mixtures of diastereomers and the individual stereoisomers, and also include pharmaceutically acceptable salts thereof. Thus compounds in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable metal cation or an organic base, for instance an amine.
  • This objective can be achieved by preparing the metal salt of the compounds with the general formula (1) as mentioned above wherein the metal ion is a lithium ion or a bivalent metal ion. Preferred bivalent metal salts are calcium, magnesium and zinc salts. Most preferred is the calcium salt.
  • The invention relates to the use of a compound of general formula (1), as defined above, for treatment and/or prophylaxis and/or preparation of pharmaceutical compositions for treatment and/or prophylaxis of optic and/or eye diseases selected from the group consisting of such diseases as e.g. (i) all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma; (ii) aquired macular disorders, preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, and microcystic macular oedema; (iii) optic neuropathy, preferably such as e.g. anterior or posterior ischemic optic neuropathy; (iv) optic neuritis; (v) uveitis, preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis; (vi) hereditary fundus dystrophies, preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy; (vii) retinal vascular diseases, preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischaemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy; (viii) scleritis and episcleritis; (ix) retinal detachments; (x) trauma to the eye globe; (xi) vitreous opacities, preferably such as e.g. vitreous hemorrhage, and asteroid hyalosis; (xii) myopia and degenerative myopia; (xiii) postsurgical trauma, preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery; (xiv) dry eye disease; (xv) corneal disorders, preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation; and corneal ectasias, preferably such as keratoconus, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.
  • Further embodiments of the invention are defined in the dependent claims.
  • The invention particularly relates to the use of compounds having general formula (4):
  • Figure US20230118503A1-20230420-C00003
  • wherein the symbols have the meanings as given above.
  • More particular, the invention relates to the use of compounds having general formula (5):
  • Figure US20230118503A1-20230420-C00004
  • wherein the symbols have the meanings as given above.
  • The most preferred active substances used according to the present invention are:
    • (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-phenylbutanoic acid (6):
  • Figure US20230118503A1-20230420-C00005
    • (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(1-naphthyl)butanoic acid (7):
  • Figure US20230118503A1-20230420-C00006
    • tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl)cyclopentyl) carbonyl]amino}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate (8):
  • Figure US20230118503A1-20230420-C00007
    • PHARMACEUTICAL COMPOSITIONS
  • The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquids or carrier materials. The pharmaceutical compositions of the invention may be administered either topically and/or systemically and in particular e.g. topically to the eye, periocularly in such manner as subconjunctival, subtenon, retrobulbar or peribulbar, intraocularly into the eye, but also enterally, orally, parenterally (intramuscularly or intravenously), subcutaneously or rectally. They can be administered in the form of solutions, suspensions, ointments (creams, gels, gel-forming solutions, sprays, ocular inserts/deposits, contact lenses), ocular implants but also tablets, capsules, softgels, powders, suppositories, nano-formulations or via iontophoresis, or by means of pharmaceutical compositions based on nanoparticle carrier systems. Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
  • Compounds of the present invention are generally administered as pharmaceutical compositions. Types of pharmaceutical compositions that may be used include but are not limited to solutions, suspensions, ointments (creams, gels or sprays), but also tablets, chewable tablets, capsules, softgels, parenteral solutions, suppositories, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The pharmaceutical compositions of the invention do not contain an aldosterone receptor antagonist.
  • In embodiments of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • Very specific formulations suitable for the compounds of the invention have been described in the patent applications WO 03/068266 and WO 04/062692.
  • The specific compounds described above are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way.
    • Eye Diseases: Delayed Retinal Cell Death in Humans and Experimental Models
  • Apoptosis is a significant component of cell death in optic and/or eye diseases including (i) all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma (R. Agarwal, S. K. Gupta, P. Agarwal, R. Saxena & S. S. Agrawal (2009) Indian J. Ophthalmol. 57, 257-266); (ii) aquired macular disorders, preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, and microcystic macular oedema (J. L. Dunaief, T. Dentchev, G.-S. Ying & A. H. Milam (2002) Arch. Ophthalmol. 120, 1435-1442); (iii) optic neuropathy, preferably such as e.g. anterior or posterior ischemic optic neuropathy (B. J. Slater, Z. Mehrabian, Y. Guo, A. Hunter & S. L. Bernstein (2008) Invest. Ophthalmol. Vis. Sci. 49, 3671-3676); (iv) optic neuritis (K. S. Shindler, E. Ventura, M. Dutt & A. Rostami (2008) Exp. Eye Res. 87, 208-213); (v) uveitis, preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis (C.-C. Chan, D. M. Matteson, Q. Li, S. M. Whitcup & R. B. Nussenblatt (1997) Arch. Ophthalmol. 115, 1559-1567); (vi) hereditary fundus dystrophies, preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy (H. Zhang, X. Li, X. Dai, J. Han, Y. Zhang, Y. Qi, Y. He, Y. Liu, B. Chang & J. J. Pang (2017) J. Ophthalmol. 2017, 1-13 9721362); (vii) retinal vascular diseases, preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy (G. Donati, A. Kapetanios, M. Dubois-Dauphin & C. J. Pournaras (2008) Acta Ophthalmol. 86, 302-306); (viii) scleritis or episcleritis (C. Heinz, N. Bograd, J. Koch & A. Heiligenhaus (2013) Graefes Arch. Clin. Exp. Ophthalmol. 251, 139-142); (ix) retinal detachments (J.G. Arroyo, L. Yang, D. Bula & D. F. Chen (2005) Am. J. Ophthalmol. 139, 605-610); (x) trauma to the eye globe (H.-C. H. Wang, J.-H. Choi, W. A. Greene, M. L. Plamper, H. E. Cortez, M. Chavko, Y. Li, J. J. Dalle Lucca & A. J. Johnson (2014) Military Med. 179, S34-S40); (xi) vitreous opacities such as e.g. vitreous haemorrhage and asteroid hyalosis (A. Alamri, H. Alkatan & I. Aljadaan (2016) Middle East African J. Ophthalmol. 23, 271-273); (xii) myopia and degenerative myopia (G. Z. Xu, W. W. Li & M. O. Tso (1996) Trans. Am. Ophthalmol. Soc. 94, 411-431); (xiii) postsurgical trauma, preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery (A. Barak, T. Goldkorn & L. S. Morse (2005) Invest. Ophthalmol. Vis. Sci. 46, 2587-2591; X. Liu, S. Ling, X. Gao, C. Xu & F. Wang (2013) JAMA Ophthalmol. 131, 1070-1072; D. Reichstein (2015) Curr. Opin. Ophthalmol. 26, 157-166); (xiv) dry eye disease (S. Yeh, X.J. Song, D. Q. Li, W. Farley, M. E. Stern & S. C. Pflugfelder (2003) Invest. Ophthalmol. Vis. Sci. 43, 124-129); (xv) corneal disorders, preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation, and corneal ectasias, preferably such as keratoconus (R. M. Kaldawy, J. Wagner, S. Ching & G. M. Seigel (2002) Cornea 21, 206-209; N. Szentmary, B. Szende & I. Suveges (2005) Eur. J. Ophthalmol. 15, 17-22). In humans, apoptosis has been demonstrated to occur in the course of glaucoma in retinal ganglion cells by means of real-time imaging using annexin 5 labelled with fluorescent dye DY-776 (M. F. Cordeiro, E. M. Normando, M. J. Cardoso, S. Miodragovic, S. Jeylani, B. M. Davis, L. Guo, S. Ourselin, R. A'Hern & P. A. Bloom (2017) Brain 140, 1757-1767). To model this kind of apoptosis in a non-human experiment, rats are subjected to systemic administration of doxorubicin and apoptosis assessed in large organs such as the liver or heart (R. Gillet, G. Grimber, M. Bennoun, C. Caron de Fromentel, P. Briand & V. Joulin (2000) Oncogene 19, 3498-3507; L.L. Fan, G. P. Sun, W. Wei, Z. G. Wang, L. Ge, W. Z. Fu & H. Wang (2010) World J. Gastroenterol. 16, 1473-1481), or rats are subjected to the action of doxorubicin in the eye and apoptosis assessed in the retinal ganglion cells (I. M. Parhad, J. W. Griffin, A. W. Clark & J. F. Koves (1984) J. Neuropathol. Exp. Neurol. 43, 188-200). We used doxorubicin-induced apoptosis in the rat to assess whether systemic administration of compounds example prevents it.
    • EXAMPLES
  • Methods: Wistar rats, 200-250 g, were anesthetized with chloral hydrate, 400 mg/kg, and osmotic minipumps, primed prior to implantation, were filled with either vehicle or example (6), representative for the compounds of the invention, in the dose of 60 mg/kg/d, and were implanted subcutaneously. Subsequently, rats (n=7) received doxorubicin in the dose of 5 mg/kg i.p. t.i.d. on days 1, 2 and 3, or rats (n=8) received doxorubicin in the dose of 5 μg or vehicle in the volume of 5 μ1 into the vitreous body of the eye by means of a Hamilton microsyringe over 5 min on the day 1. Rats were euthanized 5 days after the first i.p. injection of doxorubicin, or 5 days after the administration of doxorubicin into the vitreous body, and were transcardially perfused with a solution containing 4% paraformaldehyde in phosphate buffer. The livers and the eyes were subsequently removed and embedded in paraffin. To visualize apoptosis, a terminal deoxynucleotide transferase-mediated dUTP nick end-label (TUNEL) based staining was performed on 10 μm paraffin sections. The method of stereological disector (L. M. Cruz-Orive & E. R. Weibel (1990) Am. J. Physiol. 258, L148-L156) was used for quantification of apoptosis. An unbiased counting frame (0.05×0.05 mm, disector height 0.01 mm) was used for liver and (0.10×0.025 mm, disector height 0.01 mm) for the retinal ganglion cell layer for the sampling. The Nv of TUNEL positive cells was determined with 8-10 dissectors and is expressed as number of TUNEL positive cells×102/mm3 for liver and as number of TUNEL positive cells×103/mm3 for retinal ganglion cells. Statistical evaluation was performed by means of Student's t-test (Table 1).
  • Results: Doxorubicin caused apoptosis either in the liver or in the retina as evidenced by the presence of TUNEL positive cells (Table 1). Example (6) conferred significant protection against doxorubicin induced apoptosis in the liver and in the retina as evidenced by reduction of Nv of TUNEL positive cells vs vehicle-treated subjects (Table 1).
  • Conclusions: Example (6) decreased density of apoptotic cells in the rat liver by 23.46% and in the retina by 8.21% (Table 1). The apoptosis induced by doxorubicin in the liver was characterized by many morphological features similar to those of apoptosis seen in the retinal ganglion cells.
  • TABLE 1
    Effect on doxorubicin-induced apoptosis.
    Doxorubicin + Vehicle Doxorubicin + Example (6)
    Nv Nv
    Liver 10.36 ± 0.55 7.93 ± 0.25**
    % 100 76.54
    RGC 36.65 ± 0.36 33.64 ± 0.96* 
    % 100 91.79
    *P < 0.05,
    **P < 0.01 vs doxorubicin + vehicle; Student's t-test; RGC, retinal ganglion cells; Nv, number of TUNEL-positiv cells/mm3 ± SEM.

Claims (15)

1. Compounds of the general formula (1) wherein:
Figure US20230118503A1-20230420-C00008
R1 stands for a group with formula (2) or (3):
Figure US20230118503A1-20230420-C00009
A represents CH2, O or S,
R2 and R3 independently represent hydrogen or halogen,
R4 and R6 independently represent hydrogen or a biolabile carboxylic ester forming group;
R5 is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a (C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6)-alkoxy or halogen, and naphtyl-(C1-C6)-alkyl,
R7 and R8 independently represent hydrogen or a group forming a biolabile phosphonic acid ester,
all stereoisomers, as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment and/or for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases selected from the group consisting of such diseases as e.g. (i) all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma; (ii) aquired macular disorders, preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, and microcystic macular oedema; (iii) optic neuropathy, preferably such as e.g. anterior or posterior ischemic optic neuropathy; (iv) optic neuritis; (v) uveitis, preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis; (vi) hereditary fundus dystrophies, preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy; (vii) retinal vascular diseases, preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, and radiation retinopathy; (viii) scleritis and episcleritis; (ix) retinal detachments; (x) trauma to the eye globe; (xi) vitreous opacities, preferably such as e.g. vitreous hemorrhage, and asteroid hyalosis; (xii) myopia and degenerative myopia; (xiii) postsurgical trauma, preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, and trauma induced by cryosurgery; (xiv) dry eye disease; (xv) corneal disorders, preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, corneal vascularisation; and corneal ectasias, preferably such as keratoconus, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist, but may optionally contain either one or more of carbonic anhydrase inhibitors such as e.g. brinzolamide, α2-adrenergic agonists such as e.g. brimonidine, β-blockers such as e.g. timolol, prostaglandin analogs such as e.g. bimatoprost, rho kinase inhibitors such as e.g. netarsudil, adenosine A1 receptor agonists such as e.g. trabodenoson, ETA endothelin receptor antagonists such as e.g. sitaxentan, dual endothelin receptor antagonists such as e.g. bosentan, nitric oxide donors such as e.g. butanediol, parasympathomimetics such as e.g. pilocarpine, acetylcholine, catecholamines such as e.g. adrenaline, muscarinic receptor antagonists such as atropine, vascular endothelial growth factor inhibitors such as e.g. ranibizumab, corticosteroids such as e.g. dexamethasone, antibiotics such as e.g. vancomycin, tissue regenerating agents such as e.g. poly-carboxymethylglucose, vitamins and provitamins such as e.g. panthenol and retinyl palmitate, chemotherapeutic agents such as e.g. mitomycin, nonsteroidal anti-inflammatory drugs such as e.g. ketorolac, Hi receptor antagonists such as e.g. cetirizine, monoclonal antibodies such as e.g. adalimumab, proteases such as e.g. ocriplasmin, immunosuppressive agents such as e.g. cyclosporine, or none.
2. A compound of the general formula (4):
Figure US20230118503A1-20230420-C00010
wherein the symbols have the meanings as given in claim 1, all stereoisomers, as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment and/or for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases as claimed in claim 1.
3. A compound of the general formula (5):
Figure US20230118503A1-20230420-C00011
wherein the symbols have the meanings as given in claim 1, all stereoisomers, as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment and/or for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases as claimed in claim 1.
4. Compound (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-phenylbutanoic acid having formula (6):
Figure US20230118503A1-20230420-C00012
as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases as claimed in claim 1.
5. Compound (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-(1-naphthyl)butanoic acid having formula (7):
Figure US20230118503A1-20230420-C00013
as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment and/or for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases as claimed in claim 1.
6. Compound tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl)-carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate having formula (8):
Figure US20230118503A1-20230420-C00014
as well as pharmaceutically acceptable salts thereof, for use in the prophylaxis and/or treatment and/or for use in the preparation of pharmaceutical compositions for prophylaxis and/or treatment of optic and/or eye diseases as claimed in claim 1.
7. Use as claimed in any of the claims 1-6, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of the lithium salt, the calcium salt, the magnesium salt and the zinc salt, and that the pharmaceutically acceptable salt preferably is the calcium salt.
8. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, or malignant glaucoma.
9. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for aquired macular disorders, preferably such as e.g. age-related macular degeneration, idiopathic choroidal neovascularisation, central serous chorioretinopathy, vitreomacular interface disorders, idiopathic macular telangiectasia, cystoid macular oedema, or microcystic macular oedema.
10. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for optic neuropathy, preferably such as e.g. anterior or posterior ischemic optic neuropathy; or is for scleritis or episcleritis; or is for optic neuritis; or is for uveitis, preferably such as e.g. anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis.
11. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for hereditary fundus dystrophies, preferably such as e.g. retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform macular dystrophy, North Carolina macular dystrophy, familial dominant drusen, or concentric annular macular dystrophy.
12. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for retinal vascular diseases, preferably such as e.g. diabetic retinopathy, non-diabetic retinopathy, retinal venous occlusive disease, retinal arterial occlusive disease, ocular ischemic syndrome, hypertensive eye disease, sickle cell retinopathy, thalassemia retinopathy, retinopathy of prematurity, retinal artery macroaneurysm, primary retinal telangiectasia, Eales disease, or radiation retinopathy.
13. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for myopia, or degenerative myopia; or is for dry eye disease.
14. Use as claimed in any of the claims 1-6, characterized in that said treatment is for trauma to the eye globe; or is for postsurgical trauma, preferably such as e.g. mechanical trauma due to conventional surgery, thermotrauma due to laser surgery, or trauma induced by cryosurgery; or is for vitreous opacities, preferably such as e.g. vitreous haemorrhage, or asteroid hyalosis; or is for retinal detachments.
15. Use as claimed in any of the claims 1-6, characterized in that said prophylaxis and/or treatment is for corneal disorders, preferably such as abrasions, lacerations, ulcerations, dystrophies, opacities, endothelial and epithelial decompensation, post-surgical oedema, corneal degenerations, or corneal vascularisation; or is for corneal ectasias, preferably such as keratoconus.
US17/978,442 2020-07-19 2022-11-01 NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES Pending US20230118503A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/978,442 US20230118503A1 (en) 2020-07-19 2022-11-01 NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202016963234A 2020-07-19 2020-07-19
US17/978,442 US20230118503A1 (en) 2020-07-19 2022-11-01 NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US202016963234A Division 2020-07-19 2020-07-19

Publications (1)

Publication Number Publication Date
US20230118503A1 true US20230118503A1 (en) 2023-04-20

Family

ID=85980888

Family Applications (1)

Application Number Title Priority Date Filing Date
US17/978,442 Pending US20230118503A1 (en) 2020-07-19 2022-11-01 NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES

Country Status (1)

Country Link
US (1) US20230118503A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677297A (en) * 1995-03-23 1997-10-14 Solvay Pharmaceuticals Gmbh Benzazepine-, benzoxazepine- and benzothiazepine-n-acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them
US20030176356A1 (en) * 2001-04-24 2003-09-18 University Of North Texas Health Science Center Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677297A (en) * 1995-03-23 1997-10-14 Solvay Pharmaceuticals Gmbh Benzazepine-, benzoxazepine- and benzothiazepine-n-acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them
US20030176356A1 (en) * 2001-04-24 2003-09-18 University Of North Texas Health Science Center Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Gupta, Neeruabcd; Yücel, Yeni Habce. Glaucoma as a neurodegenerative disease. Current Opinion in Ophthalmology 18(2):p 110-114, March 2007. (Year: 2007) *

Similar Documents

Publication Publication Date Title
US20120101046A1 (en) Prophylactic or therapeutic agent for retinal disease and method for prophylaxis or therapy of retinal disease using jnk (c-jun amino-terminal kinase) - inhibitory peptide, and use of the peptide
KR101286883B1 (en) Prophylactic or therapeutic agent for corneal and conjunctival disorder
JP2021165299A (en) Pharmaceutical compositions and salts of 1,2,4-oxadiazole benzoic acid
US10688113B2 (en) Methods of treating eye pain with aminophosphinic derivatives
EP3746106B1 (en) Neutral endopeptidase (nep) and human soluble endopeptidase (hsep) inhibitors for prophylaxis and treatment of eye diseases
JPS6225645B2 (en)
US20230118503A1 (en) NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS FOR PROPHYLAXIS AND TREATMENT OF EYE DISEASES
EP1504760A1 (en) Pharmaceutical composition for prophylaxis and therapy of diseases associated with ocular fundus tissue cytopathy
US9901580B2 (en) Methods of eye treatment using therapeutic compositions containing dipyridamole
WO2018056269A1 (en) Eye drops containing jak inhibitor
US11666563B2 (en) Pharmaceutical preparation containing pyridyl aminoacetic acid compound
WO2023042851A1 (en) Medicament for preventing and/or treating dry eye
US20100120851A1 (en) Prenyltransferase inhibitors for ocular hypertension control and the treatment of glaucoma
WO2007148744A1 (en) Prophylactic or therapeutic agent for corneal/conjunctival disorder comprising fumaric acid derivative as active ingredient
WO2018056268A1 (en) Agent for treatment and/or prevention of inflammatory eye disorder
US20230355727A1 (en) Treatment of retinal disorders
WO2023150791A1 (en) Peptides and methods of use thereof in treating ocular disorders
US20150284393A1 (en) Methods for treating eye disorders
US20210047352A1 (en) NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS TO REDUCE DETRIMENTAL EFFECTS OF PERFUSION DEFICIENCY OF PARENCHYMAL ORGANS
JP2023547441A (en) NO-PDE5 inhibitors for use in the treatment of dry age-related macular degeneration, geographic atrophy and glaucoma-associated neurodegeneration
JP2006348025A (en) Prophylactic or curative agent for keratoconjunctive disorder
JP2000264847A (en) Therapeutic agent for corneal disorder
JP2008024699A (en) Prophylactic or therapeutic agent for corneal/conjunctival disorder comprising fumaric acid derivative as active ingredient
MXPA00008689A (en) Pharmaceutical composition for prophylaxis and therapy of diseases associated with ocular fundus tissue cytopathy

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER